Bis(trifluoromethyl)benzamides

ABSTRACT

BIS(TRIFLUOROMETHYL)BENZAMIDES AND BIS(TRIFLUOROMETHYL)-N-SUBSTITUTED BENZAMIDES, E.G., 2,4-BIS(TRIFLUOROMETHYL)BENZAMIDE, ARE PREPARED FROM BIS(TRIFLUOROMETHYL) BENZOIC ACIDS AND ARE USEFUL AS CENTRAL NERVOUS SYSTEM DEPRESSANTS AND COCCIDIOSTATS.

United States Patent- R 23 Claims ABSTRACT OF THE DISCLOSURE Bis(trifluoromethyl)benzamides and bis(tri-fluoromethyl)-N-substituted benzamides, e.g., 2,4-bis(triiluoromethyl)benzamide, are prepared from bis(trifiuoromethyl) benzoic acids and'are useful as central nervous system depressants and coccidiostats.

Oh (I? /Rl C-N 1,. .1 a. 0%?

Where R and R independently, represent hydrogen, lower alkyl, i.e., alkyl having 1 to 4 carbon atoms, e.g.,

methyl, ethyl, isopropyl, etc.; lower alkenyl, i.e., alkenyl having 3 or 4 carbon atoms, e.g., allyl or methallyl, lower alkynyl, i.e., alkynyl having 3 to 5 carbon atoms, e.g., propargyl; cycloalkyl having 3 to 8 ring carbon atoms, e.g., cyclopropyl, cyclohexyl, cycloheptyl and the like; benzyl;

where R is hydrogen, halo of atomic weight between about 19 to 36, or methyl;

-(CH2)DN I Rs where n is 0, 2, 3, or 4 and R and R are hydrogen, lower alkyl or phenyl; or R and R together with N represent 3-azabicyclo[2.2.1]nonane or wherein X is O, S, or NR ,'where R is hydrogen or lower alkyl, and provided that the trifiuoromethyl groups are not on adjacent carbon atoms of the benzene ring.

The CF can be in the 4, 5, or 6 position and the following amides are contemplated in this invention:

3,825,594 Patented July 23, 1974 ice whereR and R are as defined above. The compounds wherein R and R each independently represents hydrogen, lower alkenyl, lower alkynyl, cycloalkyl having 3to8carbon atoms,

phenyl or benzyl where R and R independently repre sent hydrogen or lower alkyl are especially preferred.

The process for preparing the compounds of this invention is shown in the following diagram:

where Y is a halogen having an atomic weight of about 35 to 80, and R R and the proviso are as set out above.

The product (I) is prepared by aminating an acid halide (II) with an amine (III). The reaction can be carried out in excess acid halide (II) or if desired, an inert solvent can be used. The amine (III) is normally added in the form of an aqueous or inert solvent solution; but if the amine is liquid, it can be added without dilution. The preferred inert solvents are benzene, toluene, pentane, hexane, methylene dichloride, chloroform and the like, especially toluene and methylene dichloride. Excess amine or base, e.g., potassium carbonate, can be added to absorb the acid liberated by the reaction.

Although the temperature is not critical, the reaction is preferably carried out at temperatures between 10 and 50 C., especially 20 to 35 C. For optimum results, it is preferred that the reactions be allowed to run for about 2 to 48 hours. The final product is recovered by conventional techniques, e.g., precipitation and recrystallization.

The present invention also encompasses the acid halide II which is prepared by acylating an acid corresponding to the acyl portion of compound (I) with an inorganic acid halide, e.g., SOCI PO1 PO1 or SOBr The reaction is illustrated in the following scheme using thionyl halide, the preferred acylating agents:

where Y and the proviso are as set out above.

The reaction is carried out in excess halogenating agent or inert solvent. The preferred inert solvents are benzene, toluene, pentane, hexane, heptane, methylene dichloride, chloroform and the like, especially toluene and methylene dichloride. Although the time and temperature of the reaction are not critical, it is preferred that the reaction be run for approximately 1 to 24 hours at a temperature between about 30 C. and C., and especially at the reflux temperature of the system. The acid halide may be recovered by conventional techniques, e.g.,-evaporation or distillation.

The process for preparing the compounds of formula (IV) is illustrated by the following reaction scheme:

CF; or,

C'Fa CF3 V IV recovered by conventional techniques, e.g., by recrystallization or chromatography. The acids represented by IV have the following structural formulas:

CFa

I OH

IVc

IVa IVb where (IVa), (IVb), and (IVc) are, 2,5-bis(trifiuoromethyl)benzoic acid, 2,6 bis(trifluoromethyl)benzoic acid, and 2,4-bis (trifluoromethyl) benzoic acid respectively.

The process for preparing the lithium intermediate (V) is shown by the following reaction scheme:

+ RvLi CFa CF3 VI VII V where R, is a stright chain alkyl having 1 to 6 carbon atoms, e.g. methyl, ethyl, propyl, butyl, etc., and with the provisio set out above for the trifluoromethyl groups.

The intermediate lithium compound (V) may be prepared by reacting a bis(trifluoromethyl)benzene with a straight chain lower alkyl lithium compound VII having 1 to 6 carbon atoms in an inert solvent in the presence of an inert gas. The preferred alkyl lithium compound is butyl lithium. The preferred solvents are lower hydrocarbons such as pentane, hexane, heptane, and the like, ethers such as diethyl ether, dibutyl ether, and the like, tetrahydrofuran and benzene, especially diethyl ether and hexane. The inert gas may be nitrogen, helium, argon, and the like. The reaction conveniently takes place at temperatures of -l C. to 45 C. with the preferred temperature range being C. to C.

When the starting material of formula V1 is 1,4-bis (trifluoromethyDbenzene j om-G-om the lithium intermediate has the structuralv formula When the starting material of formula V1 is 1,3-bis(trifluoromethyl)benzene (VIb) above--forthe-- trifiuoromethyl thel-ithiumintermediate can-be-represented by the structural formula -"-.-;Using" =th reaction described above for preparing .compound IV, compounds (IVa), (IVb)-and' (lVc): can be prepared. When l,4-bis(trifluoromethyDbenzene yIa) is the starting material, the 2,5bis(trifiuor'-omethyl)benzoic acid (IVa) is obtained. Starting with the l,3-bis(trifluoromethyl)benzene (VIb); amixture. of ther2,6 -bis(trifiuoromethyl)benzoic acid (IVb) and the 2,4 bis(trifluoromethyl)benzoic acid (IVc) isobtained with the'2,4' bis- (trifluoromethyl)benzoic, acid predominating. Conventional recovery techniques are utilized for 'obtainingthe products (Ia), (Ib)'and'(Ic).' L I The compounds of formulas (VI) and '(VIII) are known and many -of-the compounds of formula (III) are known and are prepared by methods disclosedin the literature. Those compounds of formula (III) not specifically disclosed are prepared according to analogous methods from known materials. I

Certain of the compounds of:formula (I) can also form mineral acid' or organic acid salts where tautomerism or the presence of a second amine group'permits. For example, where R orR is a hydrogen, tautomerism in many cases permits salt formation. 0n the other hand, when R or R is or when R and R together with N is -N N-Ro,

salts readily form because of the presence of a second amine group. I I

The compounds of formula (I). and their pharmaceutically acceptable salts in which R; and R are hydrogen are useful because they possess pharmacological properties in animals, such as mammals. In particular, these compounds are useful as central nervous system depressants and can be used as anti-convulsants as indicated by their activity in mice in which convulsive seizures have been chemically induced with'strychnine and metrazol using the method of Orlolf 'et al. (Proc, Soc. Exp. Biol., 702254, 1949).

For this use, the compounds of formula (I) in which R and R are hydrogen may be combined with a pharmaceutically acceptable carrier or adjuvant. They may be administered orally or parenterally. For this use, the dosage will vary depending upon the mode; of administration utilized and the particular compounds employed. However, in general, satisfactory results are obtained when the compounds are administered at a daily dosage of from about 1.4 milligrams to 200 milligrams per kilogram of animal body weight. This daily" dosage is preferably given in divideddoses, tag, 2 to 4 times a day, or in sustained release form. 'For'most large mammals, the total daily dosage is'from about 75 to 1000 milligrams, and dosage forms suitable for internal administration comprise from about 7.5 milligrams to about 500 milligrams of the compound in admixture with a solid or liquid pharmaceutical carrier or diluent.

A representative formulation'suitable for oral administration is a capsule prepared by standard techniques which contains the following:

Ingredient: Parts by weight 2,4-bis (trifiuoromethyl)benzamide 50 Inert filler (lactone, kaolin, starch, etc.) 250 The compounds of formula (I) are also useful in the control of poultry coccidiosis. For this purpose, the base form can be administered in the feedstuif of the birds; or

the salt form, ifstructurally possible, can be given in the drinking water. If desired, the-compounds can be given b'y'direct administration dissolved or suspended in-a suitable solve'nt. In'any event,only'minor amounts are needed 1 toobtain the=desired anti'coccidialeffect. For optimum results, it ispreferred that the base compounds be administered inthe feed of: the poultry, which is given ad libitum to=the birds. Feedconeentrations of from 0.005% to 0.3

. preferably from 0.01 to "0.1% especially from 0.03%

to 0.06%, are-recommended. I

f'EXAMPLEl Preparation of 2,5 bis(trifluoromethyl)benzoic acid A two neck round bottom flask equipped with a stirrer, dropping funnel and condenser is blanketed with nitrogen and then charged with 100 ml. of anhydrous diethyl ether and 21.4 g. (0.10 moles) of 1,4- bis(trifiuoromethyl)benzene. The solution is stirred and treated dropwise (20 minutes) with 75 ml. of n-butyllithium in hexane (0.12 moles of n-butyl lithium) at room temperature. After stir- ,ring an additional .30 minutes at room temperature the reaction mixture is poured onto 200 g. of powdered carbon dioxide. After standing overnight, the resultant semisolid is treated with 200 ml. of 2N sodium hydroxide 1 solution. The basic solution is washed with 100* ml. di-

ethyl ether, acidified with concentrated hydrochloric acid EXAMPLE 2 Preparation of 2,4-bis(trifluoromethyl)benzoic acid and 2,6-bis (trifluoromethyl) benzoic acid A two neck round bottom flask equipped with a stirrer, dropping funnel and condenser is blanketed with nitrogen and then charged with 100 ml. of anhydrous diethyl ether and 21.4 g. (0.10 mole) of 1,3-'bis(trifluoromethyl)benzene. The solution is stirred and treated dropwise min- 'utes) with 75ml. of 15% N-butyl lithium in hexane (0.12 mole of N butyl lithium) at room temperature. After stirring an additional minutes at room temperature, the reaction mixture is poured onto 200 g. of powdered carbon dioxide. After 'standing overnight the resultant semisolid is treated with 200 ml. of 2N sodium hydroxide solution. The basic solution is washed with 100 ml. of diethyl ether, acidified with concentrated hydrochloric acid and then extracted with 300 ml. chloroform. The chloroform layer is dried with sodium sulfate, filtered and concentrated in vacuo. The residue is crystallized from pentane to give 14.0 g. of a mixture of 2,6-bis(triflu0ro)benzoic acid and 2,4-bis (trifluoromethyl)benzoic acid having a melting point of 76 C.83 C. The 2,4-bis(trifiuoromethyl)benzoic acid predominates.

Treatment of the crude acid with excess diazo methane in diethyl ether gives, after removal of the ether, crude methyl esters. The methyl esters are separated by gas liquid chromatography. The first 65% of the element is refluxed for 6 hours with 2N potassium hydroxide and then acidified with crude hydrochloric acid. The mixture is extracted with methylene chloride, dried with sodium sulfate, filtered and the solvent removed in vacuo. The residue is crystallized from ether-pentane (1:1) to give 2,4- bis(trifluoromethyl)benzoic acid.

Similar treatment of later fractions of eluent yields 2,6- bis(trifluoromethyDbenzoic acid.

EXAMPLE 3 2,5-bis(trifluoromethyl)benzoyl chloride A mixture of 140 g. (0.06 moles) of 2,5-bis(trifluoromethyl)benzoic acid and 50 m1. of thionyl chloride are 6 stirred and refluxed for 1. 5 hours. The excess thionyl chloride is removed with a water pump and the residue distilled in vacuo to' give 2,5-bis (trizfluoromethyDbenzoyl chloride, b.p. to C. at .mm.

When 2,4-bis(trifluoromethy1)benzoic acid or 2,6-bis (trifluoromethyDbenzoic acid is used in place of 2,5-bis (trifluoromethyl)benzoic acid in the above process, there is obtained 2,4-bis(trifluoromethyl)benzoyl chloride and A solution containing 5.52 g. (0.04 moles) of potassium carbonate, 15 g. (0.12 moles) of 30% ammonium hydroxide in water, and 150 ml. of distilled water is titrated with 8.3 g. (0.03 mole) of 2,4-bis(trifluoromethyl)benzoyl chloride and stirred at room temperature for 16 hours. The solid product is filtered off and crystallized from a 1:1 mixture of methanol and water to give 2,4-bis(trifluoromethyl)benzamide, m.p. 152l53 C.

When 2,6-bis(trifluoromethyl)benzoyl chloride is used in place of 2,4-bis(trifiuoromethyDbenzoyl chloride in the above process, there is obtained 2,6-bis (trifluoromethyl)benzamide. When methylamine, dimethylamino anilino or p-chloroanilino is used in place of ammonia in the process of this example, there is obtained the N-methyl, N,N-dimethyl, N-phenyl, or N-p-chloro-phenyl derivatives of 2,4-bis(trifluoromethyDbenzamide, respectively.

EXAMPLE 5 2,5 -bis trifluoromethyl) benzamide A solution containing 2.5 ml. of 30% ammonium hydroxide and 150 ml. of distilled water is titrated with 8.3 g. (0.03) of 2,5-bis(trifluoromethyl)benzoyl chloride and stirred at room temperature for 16 hours. The resultant product is filtered off and crystallized from a 1:1 mixture of methanol and water. The product obtained is 2,5- bis(trifluoromethyl)benzamide; m.p. 166-168 C.

When the process of this example is carried out and methylamine, ethylamine, isopropylamine, butylamine, dimethylamine, diallyamine, N-propargylbenzylamine, aniline, diphenylamine, p-chloroaniline, p-fiuoroanilne or otoluidine is substituted for ammonia hydroxide, there is obtained respectively.

EXAMPLE 6 N ,N -dimethyl-2,5-bis(trifluoromethyl)benzoic acid hydrazide A solution of 8.3 g. (0.03 g. mole) of 2,5-bis(tn'flu0romethyl)benzoyl chloride in ml. of toluene is added to 5.4 g. (0.09 mole) of N,N-dimethyl hydrazine in ml. of toluene. The mixture is stirred at 25 C. for 16 hours. The reactants are concentrated in vacuo and the residue crystallized from 1:1 methanol-water. The product obtained is N ,N -dimethyl-2,5-bis(trifiuoromethyl)benzoic acid hydrazide; mp. -161 C. When 2,4-bis(trifluoromethyl)benzoyl chloride is substituted for 2,5-bis(trifluoromethyl)benzoyl chloride in the process above, there is obtained N ,N dimethyl-2,4-bis(trifiuoromethyDbehzoic acid hydrazide.

When hydrazine, N-methylhydrazine, or N-phenylhydrazine is used in place of N,N-dimethylhydrazine in the above process, there is obtained 2,5-bis(trifiuoromethyl) benzoic acid hydrazine, N -methyl-2,5-bis(trifiuoromethyl)benzoic acid hydrazide, or N -phenyl2,5-bis(trifiuoromethyl)benzoic acid hydrazide, respectively.

EXAMPLE 7 N- 3-dimethylaminopropyl -2,5-bis (trifluoromethyl benzamide Using the procedure of the Example 6, 9.2 g. (0.09 mole) of N,N-dimethyl-1,3-propanediamine in 150 ml. of toluene is titrated with 8.3 g. (0.07 mole) of 2,5-bis(trifluoromethyl)benzoyl chloride in 100 ml. of toluene. The mixture is stirred for 16 hours at 25 C.; and after concentrating by vacuum, the residue is crystallized from 1:1 methanol-water. The product obtained was N-(3-dimethylaminop ropyl) 2,5 bis(trifluoromethyl)benzamide; m.p. 58.560 C.

When 1,3-propanediamine is used in place of N,N-dimethyl-1,3-propanediamine in the process of this example, N-(3-aminopropyl) 2,5 bis(trifluoromethyl)benzamide is obtained.

EXAMPLE 8 N-cyclohexyl-2,5-bis (trifluoromethyl)benzamide Using the procedure of Example 6, (0.03 mol) 2,5-bis (trifluoromethyl)benzoyl chloride are added to 9.0 g. (0.09 mol) of cyclohexylamine in 100 ml. of toluene. The reactants were stirred at room temperature for about 16 hours and then concentrated on rotary vacuum. The crude product is recrystallized from 1:1 methanol-water yielding N-cyclohexyl2,5-bis(trifluoromethyl)benzamide, m.p. 157-158 C.

When cyclopropylamine or cycloheptylamine is used in place of cyclohexylamine in the process of this example, there is obtained N-cyclopropyl-2,5-bis(trifiuoromethyl) benzamide or N-cycloheptyl-2,5-bis(trifluoromethyl)benzamide. When 2,4-bis-trifluoromethyl)benzoyl chloride is substituted for 2,5 bis(trifiuoromethyl)benzoyl chloride in the process of this example, there is obtained N-cyclohexyl-2,4-bis(trifiuoromethyl)benzamide.

EXAMPLE 9 N (2,5 -bis [trifluoromethyl] benzoyl 3-azabicyclo [2.2.1]r10nane Using the procedure of Example 4, 13.8 g. (0.05 mol) of 2,5-bis(trifluoromethyl)benzoyl chloride are added to 6.9 g. (0.05 m.) of anhydrous potassium carbonate and 6.3 g. (0.05 mol) of 3-azabicyclo[2.2.1]nonane in 150 ml. of toluene. The reactants are stirred for 16 hours at 25 C. and then concentrated under vacuum. The residue is recrystallized using 1:=l methanol Water and the product obtained is N-(2,5-bis[trifiuoromethyl]benzoyl)-3- azabicyclo[2.2.1]nonane; m.p. 97100 C.

When 2,4-bis(trifiuoromethyl)benzoyl chloride is substituted for 2,5 bis(trifluoromethyl)benzoyl chloride in the above process, there is obtained N-(2,4-'bis[trifiuor0- methyl] benzoyl 3-azabicyclo [2.2. 1 ]nonane.

When the process of this example is carried out and piperazine, N-methylpiperazine, morpholine or thiomorpholine is substituted for respectively is obtained.

8 EXAMPLE 11o Following the procedure of Example 6, 8.3 'g. (0.03 mol) or 2,5-bis(trifluoromethyllbenzoyl chloride are added to 7.6 g. (0.09 mol) of 1,1-dimethylpr6pargylamine in ml. of toluene. The reactants are stirredat room temperature for about 16 hours and then concentrated on rotary vacuum. The crude produc-t'is recrystallized from 1:1 methanol water yielding N-(1,l-din1ethyl propargyl 2,5-bis'( trifluoromethyl benzamide.

When 2,4 or 2,6-bis-"(trifluoromethyl)benzoyl chloride is used in place of the 2,5-bis(trifiuoromethyl)benzoylchloride in the process of this example, there is obtained N (1,-1 dimethyl propargyl) 2,4-bis(trifluoromethyl) benzamide or N (1,1 dirnethylpropargyl)2,6-bis(trifiuoromethyl)benzamide.

What is claimed is:

1. A compound of the formula (I? /R1 C-N Where R is hydrogen, benzyl or and R is lower alkynyl; cycloalkyl having 3 to 8 ring carbons; benzyl;

where n is 0 or 3; R is hydrogen, fluorine, chlorine or methyl; and R and R are hydrogen, lower alkyl or phenyl;

provided that the trifiuoromethyl groups are not on adjacent carbon atoms of the benzene ring.

2. A compound of the formula CFa where R is propargyl, 1,-1-dimethylpropargyl, cyclopropyl,

cyclohexyl, cycloheptyl, amino, methylamino, dimethylamino, anilino, 3-aminopropyl or 3-dimethylaminopropyl, provided that the trifluo'romethyl-groups are not onadjacent carbon atoms of the benzene ring. 1

10. The compound of claim 1 which is N-(p-chlorophenyl)-2,4=bis(trifiuoromethyl)benzamide.

11. The compound of claim 2 which is 2,5-bis(trifluoromethyDbenzoic acid hydrazide.

12. The compound of claim 2 which is N -methy1-2,5- bis(trifluoromethyl)benzoic acid hydrazide.

13. The compound of claim 2 which is N -pheny1-2,'5- bis(trifiuoromethyl)benzoic acid hydrazide.

14. The compound of claim 2 which is N-(3-aminopropyl) 2,5-bis(tri-fluoromethyl)benzoic acid hydrazide.

15. The compound of claim 2 which is N-(cyclopropyl) 2,5 bis(trifluoromethyl)benzamide.

'16. The compound of claim 2 which is N-(cycloheptyl) 2,5 bis(trifluoromethyl)benzamide.

17. The compound of claim 2 which is N-(cyclohexyD- 2,4-'bis(trifluoromethyl)benzamide.

18. The compound of claim 2 which is N ,N -dimethy1- 2,5-bis(trifluoromethyDbenzoic acid hydrazide.

19. The compound of claim 2 which is N-(3-dimethylaminopropyl) -2,5-bis' trifluoromehtyl benzamide.

20. The compound of claim 2 which is N-cyclohexyl- 2,5-bis(trifluoromethyl)benzamide.

21. The compound of claim 2 which is N-(1,1-dimethylpropargyl)-2,5-bis(trifluoromethyDbenzamide.

22. The compound of claim 2 which is N-(1,1-dimethylpropargyl)-2,6-bis(trifluoromethyl)benzamide.

23. The compound of claim 2 which is N-(1,1-dimethylpropargyl)-2,4 bis(trifluoromethy1)benzamide.

References Cited UNITED STATES PATENTS 4/ 19'70 Wright et al. 26055-8 OTHER REFERENCES Yagupol skii et aL: I. General Chem. U.S.S.R., vol. 39, pp 2053-56 (September 1969) HARRY I. 'MOATZ, Primary Examiner US. Cl. X.'R.

260239 BA, 243 B, 247.7 H, 268 C, 515 R, 544 M, 558 H, 55 8 P; 424324, 246, 248, 250, 244 

